Influenza is an important cause of morbidity and mortality, and influenza vaccination is a key component of influenza prevention. Unlike many other infections, influenza viruses are constantly evolving and the vaccine components are modified to account for these changes. As a result, the effectiveness of influenza vaccine varies from year to year, and it can vary by subtype, antigenic match, and age group. Annual assessment of clinical vaccine effectiveness is needed to evaluate the impact of national vaccine recommendations and policies, understand the relationship between antigenic changes in viruses and clinical protection, and prepare for vaccine assessment during a pandemic. Interim, mid-season estimates of vaccine effectiveness are useful for public health agencies and physicians. To estimate vaccine effectiveness, patients with acute respiratory illness (fever, feverishness or cough) will be enrolled from a predefined population cohort during the influenza season. Enrollment will occur during or after an outpatient, urgent care or emergency department encounter. Most enrollments will occur at the point of care, but some patients will be contacted by phone and screened for eligibility on the day after receiving a diagnosis for acute respiratory illness. After obtaining informed consent, nose and throat swabs will be tested for influenza A and B using a nucleic acid amplification test (RT-PCR). Viral cultures will be performed on positives, and a subset will be sent to CDC for antigenic characterization. Influenza immunization status will be determined by a validated immunization registry. Vaccine effectiveness will be calculated using a case control approach where cases include participants with RT-PCR confirmed influenza and controls include study participants with non-influenza respiratory illness (negative RT-PCR). Severity will be assessed by obtaining data on hospital admissions and x-ray confirmed pneumonia episodes. Data will provided to CDC for combined analyses with other participating sites, including mid-season data for interim analysis of effectiveness. Separate estimates of vaccine effectiveness will be calculated for different age groups, for each influenza type/subtype, and for high risk individuals. We will estimate the population-based attack rate for medically attended influenza in vaccinated and unvaccinated individuals. The proposed research will 1) generate data to support and inform physician practice and public health agency recommendations for influenza prevention, 2) increase our understanding of antigenic distance and its relationship to clinical vaccine effectiveness, and 3) provide a platform to measure VE and study the epidemiology of influenza during a pandemic.